The present invention relates to gene directed enzyme prodrug therapy (GDEPT) and its use in the treatment of disease, including tumours.
A therapeutic approach termed "virus-directed enzyme prodrug therapy" (VDEPT) has been proposed as a method for treating tumour cells in patients using prodrugs. Tumour cells are targeted with a viral vector carrying a gene encoding an enzyme capable of activating a prodrug. The gene may be transcriptionally regulated by tissue specific promoter or enhancer sequences. The viral vector enters tumour cells and expresses the enzyme, in order that a prodrug is converted to an active drug within the tumour cells (Huber et al, Proc. Natl. Acad. Sci. USA (1991) 88, 8039). Alternatively, non-viral methods for the delivery of genes have been used. Such methods include calcium phosphate co-precipitation, microinjection, liposomes, direct DNA uptake, and receptor-mediated DNA transfer. These are reviewed in Morgan & French Anderson, Annu. Rev. Biochem., 1993,62;191. The term "GDEPT" (gene-directed enzyme prodrug therapy) is used to include both viral and non-viral delivery systems.
The success of a GDEPT system relies upon two limiting factors. The system requires cells which need to be targeted by the vector to be infected. If a cell does not become infected then no active drug will be produced within it so that in order to be killed active drug will need to enter it by a bystander effect, having been produced in another infected cell. Not all active drugs when produced inside a cell will be capable of leaving that cell in order to do this. Further, it is a requirement that the prodrug enters the cell. Some prodrugs may not be capable of crossing the membrane of a cell.